Cox D N, Davidson V P, Judd C E, Stodgell C, Traiger G J
Department of Pharmacology and Toxicology, University of Kansas, Lawrence 66045-2505.
Toxicol Appl Pharmacol. 1992 Apr;113(2):246-52. doi: 10.1016/0041-008x(92)90121-8.
Para-Methylthiobenzamide (PMTB) produces injury to the liver and kidney. Toxicity is mediated via its biotransformation to a reactive S,S-dioxide metabolite. The objective of this study was to examine the role of hepatic metabolism in the production of PMTB-induced renal toxicity. Renal injury was assessed in partially hepatectomized and sham-operated rats and the effect of this procedure on the distribution and metabolism of PMTB was examined. The in vitro oxidation of PMTB and [14C]thiobenzamide by rat kidney microsomes was also examined. Plasma urea levels and renal cortical slice uptake of organic ions were used to monitor renal function. Partial hepatectomy alone did not alter renal function nor raise blood urea nitrogen levels. Nephrotoxicity resulted when a nonnephrotoxic dose of PMTB (1.2 mmol/kg) was given to partially hepatectomized rats. An HPLC method was used for measurement of PMTB and its metabolites para-methylthiobenzamide S-oxide (PMTBSO) and para-methylbenzamide (PMBA) in plasma and kidney. Hepatectomy delayed the removal of this dose of PMTB from plasma and allowed greater concentrations of PMTB and PMTBSO to accumulate in plasma and kidney at 6 and 15 hr. The level of PMBA was similar in both groups at 6 hr, but was increased in plasma and kidney of the hepatectomized group at 15 hr. Kidney microsomes rapidly converted PMTB to PMTBSO and small amounts of PMBA. [14C]TB was oxidized by microsomes to thiobenzamide S-oxide, benzamide, and covalently bound metabolites. The results indicate that partial hepatectomy lowered the threshold for the expression of nephrotoxicity by PMTB. This procedure is associated with an increased renal accumulation of PMTB and PMTBSO, which are both sequentially transformed to the toxic metabolite.
对甲基硫代苯甲酰胺（PMTB）会对肝脏和肾脏造成损伤。其毒性是通过生物转化为具有反应性的S,S-二氧化物代谢产物介导的。本研究的目的是探讨肝脏代谢在PMTB诱导的肾毒性产生中的作用。在部分肝切除和假手术大鼠中评估肾损伤，并检查该手术对PMTB分布和代谢的影响。还研究了大鼠肾微粒体对PMTB和[14C]硫代苯甲酰胺的体外氧化作用。采用血浆尿素水平和肾皮质切片对有机离子的摄取来监测肾功能。单独的部分肝切除术不会改变肾功能，也不会提高血尿素氮水平。当给部分肝切除的大鼠给予非肾毒性剂量的PMTB（1.2 mmol/kg）时会导致肾毒性。采用高效液相色谱法测定血浆和肾脏中的PMTB及其代谢产物对甲基硫代苯甲酰胺S-氧化物（PMTBSO）和对甲基苯甲酰胺（PMBA）。肝切除术延迟了该剂量的PMTB从血浆中的清除，并使血浆和肾脏中PMTB和PMTBSO在6小时和15小时时积累到更高浓度。两组在6小时时PMBA水平相似，但在15小时时肝切除组的血浆和肾脏中PMBA水平升高。肾微粒体迅速将PMTB转化为PMTBSO和少量PMBA。[14C]TB被微粒体氧化为硫代苯甲酰胺S-氧化物、苯甲酰胺和共价结合的代谢产物。结果表明，部分肝切除术降低了PMTB肾毒性表达的阈值。该手术与PMTB和PMTBSO在肾脏中的积累增加有关，它们都会依次转化为有毒代谢产物。
